The goal of this proposal is to identify new strategies which can offer more selective symptomatic treatment for Parkinson's disease (PD) by targeting non-dopaminergic signaling pathways. One relatively understudied yet promising candidate for second messenger-based therapies is the soluble guanylyl cyclase (sGC)-cGMP signaling cascade. Our published data show that acute pharmacological inhibition of sGC can effectively normalize the following: (i) elevated cGMP levels observed in the DA-depleted striatum, (ii) abnormal increases in striatal medium-sized spiny neuron (MSN) activity, (iii) elevated metabolic activity in the subthalamic nucleus, and (iv) the reduction in adjusting steps (i.e., forelimb akinesia) induced by DA denervation. Interestingly, the net effect of these complex neuroadaptations induced by striatal DA depletion can be transiently mimicked by acute D2 receptor antagonism, thereby indicating that loss of DA tone results in preferential upregulation of cGMP synthesis in D2 receptor- expressing striatopallidal neurons. Therefore, our central hypothesis is that chronic downregulation of sGC-cGMP signaling is sufficient to rescue motor impairments observed in DA-depleted animals, primarily by preventing abnormal striatopallidal output. In support of this hypothesis, our preliminary data show that chronic (7 day) administration of a selective sGC inhibitor is sufficient to improve stepping performance in DA-depleted rats, an effect which was found to persist at least 72 hours after the last ODQ injection. Thus, the rationale for the proposed work is that chronic pharmacological manipulation of sGC-cGMP signaling and downstream targets may be a powerful approach for: 1) restoring functional alterations in striatal output induced by DA depletion, and 2) treating PD-associated motor deficits. Two Specific Aims are proposed: Aim 1 will determine the mechanism(s) by which downregulation of sGC- cGMP signaling rescues pathological function associated with DA denervation. Aim 2 will determine whether pharmacological attenuation of sGC-cGMP signaling enhances the antiparkinsonian actions of L-DOPA. Overall, the proposed studies will have an important positive impact because they will generate vital information regarding the modulatory influence of sGC-cGMP signaling on synaptic mechanisms involved in the regulation of corticostriatal transmission and motor behavior in the intact and DA-depleted striatum. Moreover, successful completion of these Specific Aims will reveal promising new therapeutic strategies (i.e., down regulation of striatopallidal output using selective sGC-cGMP-PKG pathway inhibitors), which could be used as monotherapy or in combination with L-DOPA for treating PD.